Stuart Shearer

HIV-1 and recurrence, relapse, and reinfection of tuberculosis after cure: a cohort study in South African mineworkers

BACKGROUND The proportion of recurrent tuberculosis cases attributable to relapse or reinfection and the risk factors associated with these different mechanisms are poorly understood. We followed up a cohort of 326 South African mineworkers, who had successfully completed treatment for pulmonary tuberculosis in 1995, to determine the rate and mechanisms of recurrence. METHODS Patients were examined 3 and 6 months after cure, and then were monitored by the routine tuberculosis surveillance system until December, 1998. IS6110 DNA fingerprints from initial and subsequent episodes of tuberculosis were compared to determine whether recurrence was due to relapse or reinfection All patients gave consent for HIV-1 testing. FINDINGS During follow-up (median 25.1 months, IQR 13.2-33.4), 65 patients (20%) had a recurrent episode of tuberculosis, a recurrence rate of 10.3 episodes per 100 person-years at risk (PYAR)-16.0 per 100 pyar in HIV-1-positive patients and 6.4 per 100 pyar in HIV-1-negative patients. Paired DNA fingerprints were available in 39 of 65 recurrences: 25 pairs were identical (relapse) and 14 were different (reinfection). 93% (13/14) of recurrences within the first 6 months were attributable to relapse compared with 48% (12/25) of later recurrences. HIV-1 infection was a risk factor for recurrence (hazard ratio 2.4, 95% CI 1.5-4.0), due to its strong association with disease caused by reinfection (18.7 2.4-143), but not relapse (0.58; 0.24-1.4). Residual cavitation and increasing years of employment at the mine were risk factors for relapse. INTERPRETATION In a setting with a high risk of tuberculous infection, HIV-1 increases the risk of recurrent tuberculosis because of an increased risk of reinfection. Interventions to prevent recurrent disease, such as lifelong chemoprophylaxis in HIV-1-positive tuberculosis patients, should be further assessed.

How Soon after Infection with HIV Does the Risk of Tuberculosis Start to Increase? A Retrospective Cohort Study in South African Gold Miners

BACKGROUND Infection with human immunodeficiency virus (HIV) increases the risk of tuberculosis (TB), but no study has assessed how this risk changes with time since HIV seroconversion. METHODS The incidence of pulmonary TB was estimated in miners with and those without HIV infection in a retrospective cohort study. HIV test results were linked to routinely collected TB, demographic, and occupational data. The rate ratio (RR) for the association between HIV status and TB was estimated by time since HIV seroconversion, calendar period, and age. RESULTS Of the 23,874 miners in the cohort, 17,766 were HIV negative on entry, 3371 were HIV positive on entry, and 2737 seroconverted during follow-up (1962 had a seroconversion interval of < or =2 years). A total of 740 cases of TB were analyzed. The incidence of TB increased with time since seroconversion, calendar period, and age. TB incidence was 2.90 cases/100 person-years at risk (pyar) in HIV-positive miners and was 0.80 cases/100 pyar in HIV-negative miners (adjusted RR, 2.9 [95% confidence interval {CI}, 2.5-3.4]). TB incidence doubled within the first year of HIV infection (adjusted RR, 2.1 [95% CI, 1.4-3.1]), with a further slight increase in HIV-positive miners for longer periods, up to 7 years. CONCLUSION The increase in the risk of TB so soon after infection with HIV was unexpected. Current predictive models of TB incidence underestimate the effect of HIV infection in areas where TB is endemic.

Tuberculosis control and molecular epidemiology in a South African gold-mining community

BACKGROUND Gold miners have very high rates of tuberculosis. The contribution of infections imported into mining communities versus transmission within them is not known and has implications for control strategies. METHODS We did a prospective, population-based molecular and conventional epidemiological study of pulmonary tuberculosis in a group of goldminers. Clusters were defined as groups of patients with Mycobacterium tuberculosis isolates with identical IS6110 DNA fingerprints. We compared the frequency of possible risk factors in the clustered and non-clustered patients whose isolates had fingerprints with more than four bands, and re-interviewed members of 45 clusters. FINDINGS Of 448 patients, ten were excluded because they had false-positive cultures. Fingerprints were made in 419 of 438, of which 371 had more than four bands. 248 of 371 were categorised into 62 clusters. At least 50% of tuberculosis cases were due to transmission within the community. Patients who had failed treatment at entry to the study were more likely to be in clusters (adjusted odds ratio 3.41 [95% CI 1.25-9.27]). Patients with multidrug-resistant isolates were more likely to have failed treatment but were less likely to be clustered than those with a sensitive strain (0.27 [0.09-0.83]). HIV infection was common (177 of 370 tested) but not associated with clustering. INTERPRETATION Despite a control programme that cures 86% of new cases, most tuberculosis in this mining community is due to ongoing transmission. Persistently infectious individuals who have previously failed treatment may be responsible for one third of tuberculosis cases. WHO targets for cure rates are not sufficient to interrupt transmission of tuberculosis in this setting. Indicators that are more closely linked to the rate of ongoing transmission are needed.

High Rates of Recurrence in HIV-Infected and HIV-Uninfected Patients with Tuberculosis

BACKGROUND The rate of recurrent tuberculosis disease due to reinfection, compared with the incidence of new tuberculosis, in those with and without HIV infection is not known. METHODS In a retrospective cohort study of South African gold miners, men with known dates of seroconversion to HIV (from 1991 to 1997) and HIV-negative men were followed up to 2004. Rates of tuberculosis recurrence >2 years after the first episode were used as a proxy for reinfection disease rates. RESULTS Among 342 HIV-positive and 321 HIV-negative men who had had 1 previous episode of tuberculosis, rates of recurrence were 19.7 cases per 100 person-years at risk (PYAR; 95% confidence interval [CI], 16.4-23.7) and 7.7 cases per 100 PYAR (95% CI, 6.1-9.8), respectively. The recurrence rate did not vary by duration of HIV infection. Recurrent pulmonary tuberculosis rates >2 years after the first episode were 24.4 cases per 100 PYAR (95% CI, 17.2-34.8) in HIV-positive men and 4.3 cases per 100 PYAR (95% CI, 2.2-8.3) in HIV-negative men, compared with incidence rates of new pulmonary tuberculosis of 3.7 cases per 100 PYAR (95% CI, 3.3-4.1) in HIV-positive men and 0.75 cases per 100 PYAR (95% CI, 0.67-0.84) in HIV-negative men in the same cohort. CONCLUSIONS Tuberculosis recurrence rates, likely due to reinfection, were much higher than incidence rates. The findings suggest heterogeneity in susceptibility, implying that a vaccine could still provide useful protection in the population and strengthening the case for secondary preventive therapy.

Effects of duration of HIV infection and secondary tuberculosis transmission on tuberculosis incidence in the South African gold mines.

Background:HIV increases the risk of tuberculosis directly, through immunosuppression, and indirectly, through onward transmission of Mycobacterium tuberculosis from the increased caseload. We assess the contribution of these two mechanisms by time since seroconversion to HIV. Methods:The incidence of new pulmonary tuberculosis was estimated in a retrospective cohort study of South African gold miners over 14 years. HIV tests were done in random surveys in 1992–1993, and in clinics. One thousand nine hundred fifty HIV-positive men with seroconversion intervals of less than 3 years were identified and linked to medical, demographic and occupational records. They were compared with men who were HIV-negative in a survey, with no later evidence of HIV. Analyses were censored when men were diagnosed with tuberculosis, died or left the mine. Results:Tuberculosis incidence rose soon after HIV infection, reaching 1.4/100 person-years (95% confidence interval 1.1–1.9) within 2 years, and 10.0/100 person-years (95% confidence interval 6.5–15.5) at 10 or more years. By 11 years from seroconversion, nearly half the men had had tuberculosis. Among 5702 HIV-negative men, tuberculosis incidence was 0.48/100 person-years (95% confidence interval 0.33–0.70) in 1991–1993 and doubled over the period of the study (after adjusting for age). Age-adjusted model estimates suggest that half the increase in tuberculosis incidence by time since HIV infection was attributable to increasing incidence over calendar period – the indirect effect. Conclusion:For the first time, we have shown that the increase in tuberculosis risk by time since seroconversion reflects both direct effects of HIV increasing susceptibility, and indirect effects due to onward transmission. Innovative and sustained public health measures are needed to reduce Mycobacterium tuberculosis transmission.

Cause of death and presence of respiratory disease at autopsy in an HIV-1 seroconversion cohort of southern African gold miners

Objectives:To describe causes of death and respiratory infections in HIV-infected miners in the pre-antiretroviral era, by duration of HIV infection. Design:A retrospective cohort of 1950 gold miners with known dates of HIV seroconversion and 6164 HIV-negative miners was followed from the early 1990s to 2002. Methods:Causes of death were available from multiple sources: personnel records, clinical records, death certificates and autopsies of cardiorespiratory organs performed for compensation purposes. Results:Causes of death were known for 279 of 308 HIV-positive (91%) and 234 of 254 HIV-negative (92%) men who died while employed or within 6 months of leaving employment. The mortality rate from unnatural causes was similar in HIV-positive and HIV-negative miners and by duration of HIV infection. Among deaths from natural causes, 87% in HIV-positive and 41% in HIV-negative individuals were caused by infection (P < 0.001); 47% of HIV-positive and 26% of HIV-negative individuals had tuberculosis. The proportion of deaths from natural causes with any infection, or with specific infections (tuberculosis, cryptococcus, pneumocystis), did not vary with the duration of HIV infection. Autopsies were performed on 29% of men who died from natural causes: 83% of HIV-positive and 37% of HIV-negative men had respiratory infections (P < 0.001), half of which were clinically undiagnosed. Conclusion:Tuberculosis was the leading cause of death in HIV-positive and negative men who died from natural causes. Although the mortality rate from natural causes increased greatly with the duration of HIV infection, the pattern of disease hardly changed, suggesting that slow and fast progressors succumb to the same range of diseases.

Survival from HIV-1 seroconversion in Southern Africa : a retrospective cohort study in nearly 2000 gold-miners over 10 years of follow-up

Objective:To obtain robust estimates of survival with HIV in individuals with known dates of seroconversion in Africa in the pre-antiretroviral era. Design and methods:Mortality rates were estimated in men from four South African gold mines in a retrospective cohort study with 10-year follow-up. HIV testing was carried out with counselling and consent, in random surveys in the early 1990s and in clinics. A total of 1950 HIV-positive men with seroconversion intervals < 3 years were compared with 6164 HIV-negative men with no subsequent evidence of HIV. Unique industry numbers were used to link medical records to demographic and occupational information. Follow-up after leaving the mine was conducted through employment offices across southern Africa, and using South African death registration data. Results:Follow-up was complete for 85% of those who seroconverted. Median survival was 10.5 years overall: 11.5 years for those aged 15–24 at seroconversion, 10.5 years for those aged 25–34, 9.5 years for those aged 35–44, and 6.3 years for those aged 45+ years. The relative mortality rate in comparison with HIV-uninfected miners increased quickly, reaching 13 for those HIV-infected for at least 9 years, and did not vary by age group. Excess mortality increased with age and duration of infection to > 10% per year. Adjusted to age 25–29 years at seroconversion, 5-year survival was 89% and 10-year 62%. Discussion:This study reports by far the largest cohort of individuals with known dates of seroconversion available in Africa. After adjusting for age, the survival pattern was similar to that seen in the West before antiretroviral therapy was available.

Tuberculosis treatment failure and drug resistance--same strain or reinfection?

Tuberculosis patients may have Mycobacterium tuberculosis in their sputum at the end of treatment, and may show new drug resistance, due to either inadequate treatment of the original episode or reinfection with a new strain during therapy. In a cohort study of mineworkers with tuberculosis in South Africa, 57 of 438 patients had positive sputum cultures 6 months after recruitment in 1995. Of the 31 patients who initially had fully sensitive strains, 3 developed multidrug resistance (MDR) and 3 single-drug resistance (SDR). Of the 6 who started with SDR, 3 became MDR. HIV infection was not associated with drug resistance at enrollment or 6 months later. We compared pairs of DNA fingerprints from isolates of M. tuberculosis at recruitment and 6 months later in the 48 patients for whom we had both available. In 45, the pairs were identical. In 1 patient, although both isolates were fully sensitive, the later fingerprint had 1 less band (transposition). In 2 pairs, the fingerprint patterns were completely different: one seemed to be the result of laboratory error and the other was a true reinfection with an MDR strain. Despite a high risk of infection, with a moderate proportion of background drug-resistant strains (11% SDR, 6% MDR), reinfection is not a common cause of treatment failure or drug resistance at 6 months.

Effect of HIV on work-related injury rates in South African gold miners

Objective:Work-related injuries have severe, well-documented economic and social impacts, and injury is a leading cause of death in working adults. As adults of working age are one of the groups most affected by the HIV epidemic, the interaction between work-related injuries and HIV is important. The objective was to calculate the effect of HIV on the rate and severity of work-related injuries by duration of infection. Design and methods:A large, retrospective seroincident cohort of South African gold miners was studied. Data routinely collected by the mines, and assurance company injury data were analysed. HIV-positive and negative miners were compared, allowing the calculation of injury rates and rate ratios. Severity of injuries was measured by the number of days away from work, percentage of permanent disability, and fatalities. Results:Results were available for 1661 HIV-positive and 6166 HIV-negative miners over 10 years. HIV infection increased the rate of work-related injuries overall (adjusted rate ratio, 1.3; 95% confidence interval, 1.1–1.4), but had less effect on severe injuries. Injury rates in HIV-positive men prior to the first positive test were similar to those in HIV-negative men. The injury rate rose soon after the first HIV positive test. After seroconversion there was only weak evidence of an increase in injury rates by duration of infection. Conclusion:This is the first study to demonstrate an increase in injury rates in HIV-positive individuals. The increase may reflect direct effects of HIV infection as well as behaviour change once HIV is diagnosed.

The effect of HIV infection on time off work in a large cohort of gold miners with known dates of seroconversion

Objectives To estimate the effect of HIV infection on time off work. To provide baseline estimates for economic and actuarial models, and for evaluations of ART and other workplace interventions. Methods A retrospective cohort study of gold miners with known dates of seroconversion to HIV, and an HIV-negative comparison group, used routinely collected data to estimate the proportion of time off work by calendar period (1992–2002, prior to the introduction of ART), age, time since seroconversion and period before death. The authors calculated ORs for overall time off work and RR ratios (RRR, using multinomial logistic regression) for reasons off work relative to being at work. Results 1703 HIV-positive and 4859 HIV-negative men were followed for 34 424 person-years. HIV-positive miners spent a higher proportion of time off work than negative miners (20.7% vs 16.1%) due to greater medical and unauthorised absence. Compared with HIV-negative miners, overall time off work increased in the first 2 years after seroconversion (adjusted OR 1.40 (95% CI 1.36 to 1.45)) and then remained broadly stable for a number years, reaching 38.8% in the final year before death (adjusted OR 3.27, 95% CI 2.95 to 3.63). Absence for medical reasons showed the strongest link to HIV infection, increasing from an adjusted RRR of 2.66 (95% CI 2.45 to 2.90) for the first 2 years since seroconversion to 13.6 (95% CI 11.8 to 15.6) in the year prior to death. Conclusions Time off work provides a quantifiable measure of the effect of HIV on overall morbidity. HIV/AIDS affects both labour supply (increased time off work) and demand for health services (increased medical absence). The effects occur soon after seroconversion and stabilise before reaching very high levels in the period prior to death. Occupational health services are an important setting to identify HIV-infected men early.